Alzheimer's Disease (AD) is the most common form of dementia, a chronic, neurodegenerative disorder characterized by a loss of cognitive ability, severe behavior abnormalities, and death. It affects roughly 10% of the population over age 65 and 40% of those over age 85. Unlike other leading causes of death such as heart disease, cancer and stroke, mortality from Alzheimer's disease will escalate dramatically over the next two to three decades as advances in medical technology permit more individuals to reach the age of risk for dementias. In the United States, 7-8% of all medical costs are related to dementia today. There are currently 2.5 to 4.0 million patients living with AD in the U.S. and 17 to 25 million worldwide. There is no definitive treatment or cure for this devastating disease.
As originally defined by Alois Alzheimer (1907), two microscopic deposits, i.e., the neurofibrillary tangle and the senile amyloid plaque, remain the pathologic hallmarks of the disease. The definitive diagnosis of Alzheimer's disease has traditionally required either biopsy or postmortem histopathology. With the recent introduction of ligands labeling amyloid plaques with positron emitting isotopes, combined with cognitive testing and measurements of specific molecules in the spinal fluid, more definitive diagnosis of this disease has now become available without histopathology.
Considerable evidence has been accumulated suggesting that the β-amyloid (Aβ) peptide-the major component of senile amyloid plaques—plays an important role in AD. An updated review on the β-amyloid (Aβ) peptide (as of Feb. 13, 2013) is available from Wikipedia at en.wikipedia.org/wiki/Beta_amyloid#cite_note-wales2010-41 which link is included here by reference. Successful disease-modifying therapy for AD is likely to include products that affect the deposition of β-amyloid in the brain. A recent publication by Morgan, D. on “Immunotherapy for Alzheimer's Disease” (Morgan D. J Int Med 2011; 269:54-63), which is relevant to this invention is included by reference as a review of the field.
The initiating factor, necessary but not sufficient for Alzheimer's disease, is the accumulation of amyloid aggregates consisting of the Aβ peptide. The genetics of familial forms of Alzheimer's disease and Down's syndrome cases (which result in precocious Alzheimer pathology) have overproduction of a longer C-terminal form of the Aβ peptide (42 amino acids in length) as a common element. This Aβ1-42 peptide is prone to form beta sheet structures and aggregate into oligomers and fibrils. These amyloid deposits may be present a decade or longer in the brain prior to the initiation of the cognitive symptoms of the disorder. A second step in the pathogenesis of the disease is the formation of intraneuronal neurofibrillary tangles from hyperphosphorylated microtubule binding protein tau. Other neurodegenerative disorders can also be formed by the tau pathology in the absence of amyloid deposits, but they differ from Alzheimer's both in clinical presentation and in the location of the pathology regionally in the brain. In tau transgenic mouse models, the tau deposits can be precipitated by intracranial injection of amyloid or breeding with mice producing Aβ deposits. Moreover, interrupting the amyloid deposition with anti-Aβ immunotherapy can diminish the progression of tau pathology in mice expressing multiple transgenes. The tau pathology appears to be better correlated with cognitive status than the amyloid pathology, consistent with it being the more proximal cause of the mental dysfunction. By uncertain mechanisms, these pathologies result in the loss of synaptic function, synapses, and ultimately a loss of neurons leading to considerable brain atrophy.
There are multiple hypotheses regarding the mechanistic steps involved. The intermediate sized aggregates of amyloid and/or tau, referred to as oligomers, are considered a more direct cause of toxicity. Even in the earliest stages of the disorder, the “mild cognitive impairment” (MCI) phase, there appears to be considerable accumulation of plaque and tangle pathology, and neuron loss. These observations suggest that treating the disorder at the earliest possible stages, much as is done with cardiovascular disease, will be essential to controlling Alzheimer's disease.
In 1999, a vaccine approach was found to reduce amyloid deposits in transgenic mice overproducing the amyloid precursor protein. Thereafter, vaccines or passive immunotherapy targeting Aβ were found to rescue memory deficits in these mice. Aβ-specific antibodies, actively generated by the immune system or passively administered, consistently reduce plaque burden in different transgenic mouse models for Aβ-amyloidosis. Given the success of vaccination in animal models, and the lack of any alternative disease modifying therapy for Alzheimer's disease, a first clinical attempt to stimulate the immune system of AD patients to generate Aβ-antibody was initiated with a vaccine termed AN1792, which consisted of full length Aβ1-42 peptide containing both B and T cell epitopes, aggregated into fibrils. About 60 patients were treated with one or more doses of the vaccine in a phase 1 safety trial. One of the initial observations was a variable antibody response, with many patient vaccines failing to generate detectable antibody titers against the target Aβ peptide antigen. This lack of immune response in many of the patients led to a change of vaccine formulation to include QS-21 as the adjuvant in an attempt to enhance the immunogenicity of the AN1792 vaccine formulation in the phase 2 safety and immunogenicity trial. The goal was to immunize patients to a preset antibody titer through multiple inoculations. However, the immunizations were halted within a short time of initiating the trial due to a small percentage of the patients (˜6%) developing aseptic meningoencephalopathy, an inflammatory reaction in the Central Nervous System (CNS). Two patients who developed these symptoms of CNS inflammation died with subsequent autopsies revealing a T cell infiltration of the CNS, apparent with signs of meningeal inflammation. It was concluded that the adverse response of the AN1792 vaccine formulation was an autoimmune reaction caused by the vaccine (Orgogozo J M, et al., Neurology 2003; 61:46-54). From an efficacy viewpoint, no differences in the rate of brain shrinkage by MRI or cognitive performance were observed between the vaccines and those receiving placebo vaccine.
Despite the AN1792 vaccine set back, the development of novel vaccine strategies and adjuvants against the Aβ peptide for immunotherapy of Alzheimer's disease has been an area of intense creativity. In most instances, the goal has been to develop B cell activation and antibody production, with minimal T cell involvement (at least against Aβ), due to the adverse events found in human trials with vaccines against the full length Aβ1-42 peptide as shown in the AN1792 case.
Currently, aside from the product of this invention managed by the inventor and her team, there are four Phase I/II clinical trials of active immunization employing various vaccine designs and formulations targeting Aβ fragments. These trials include: ACC-001 (Elan Corporation Inc. and Wyeth) using as immunogen the Aβ1-7 amino-terminal peptide fragment conjugated to a diphtheria toxoid protein; CAD106 (Immunodrug™; Cytos Biotechnology AG and Novartis Pharma AG) using as immunogen the Aβ1-5 amino-terminal peptide fragment coupled to Qβ virus-like particle; V950 (Merck) using as immunogen Aβ amino-terminal peptides conjugated to ISCO-MATRIX; and GSK/Affiris using as immunogen Aβ peptide mimetics conjugated to carrier molecules. In addition, there are other vaccine approaches targeting Aβ as described in a review by Tabira T (Tohoku J Exp Med 2010; 220:95-106).
All vaccine designs and formulations targeting Aβ currently in human trials, as described above, suffer from weak immunogenicity with variable antibody response in that only from 30% to approximately 70% to 80% of patients receiving these vaccines developed antibodies towards the target Aβ peptide, which makes any further analysis of efficacy resulting from the vaccine generated anti-Aβ antibodies more complicated. Most of the vaccine designs are complicated, requiring conjugation of the very short Aβ peptide fragments to a large protein or viral particle like carrier, thus directing most of the antibody responses towards the undesired carrier rather than the short target peptides; complicated vaccine designs dictate extensive manufacturing procedures, thus difficult in quality control and not cost-effective. These vaccines are uncertain in their safety characteristics due to the potential Th1 activation property of the adjuvant and formulation used. In addition, as of this date, none of these vaccines has shown any clinical efficacy such as improvement in cognition functions in patients receiving the vaccines.
In developed countries, AD is one of the most costly diseases to society. New therapies must be found to prevent, delay the onset, or slow the progression of AD. Despite the promising findings of immunological interventions in mice for AD, a safe and efficacious human vaccine targeting Aβ for prevention and treatment of dementia of Alzheimer's type remains a challenge. In view of the limitations of vaccine designs and formulations currently in preclinical or clinical trials as discussed above, there is an unmet and urgent need for the development of a safe and efficacious vaccine formulation to provide broadly responsive immunotherapy for prevention and treatment of dementia of the Alzheimer's type. When such a vaccine formulation is successful against Alzheimer's pathology, it will become among the standard approaches to preventing the disease.